Charge-transfer-directed radical substitution enables para-selective C–H functionalization

Abstract

Efficient C–H functionalization requires selectivity for specific C–H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho- and meta- selectivity, but a general strategy for para-selective C–H functionalization has remained elusive. Herein, we introduce a previously unappreciated concept which enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit areneto-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate that the selectivity is predictable by a simple theoretical tool and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of charge transfer directed radical substitution could serve as the basis for the development of new, highly selective C–H functionalization reactions.

Organoselenium‐Catalyzed Regioselective C−H Pyridination of 1,3‐Dienes and Alkenes

“…[13] Therefore,functionalization of pyridine groups with 1,3-dienes is highly valuable.With this in mind, we envisioned that pyridine could serve as an ucleophile to attack as eleniranium ion, resulting in the formation of pyridinium salt as the product. [14] Although there is no report related to the attack of free pyridine towards seleniranium ion in the literature, [15] the stability of pyridinium salts might drive the occurrence of oxidation-elimination. [14] Although there is no report related to the attack of free pyridine towards seleniranium ion in the literature, [15] the stability of pyridinium salts might drive the occurrence of oxidation-elimination.…”

Radical Carbofluorination of Alkenes with Arylhydrazines and Selectfluor: Additives, Mechanistic Pathways, and Polar Effects

“…Combining these two substructures, our first suggestion was compound 17,w hich could, however,r eadily be ruled out by the synthesis of an authentic sample. [17] The next candidate, which appeared plausible because of its assumablei nstability, and which might result from an undesired attack of radical dication 3 on hydrazine 5b,w as compound 18.B ecause 18 should,h owever,a lso be formed in the absence of the alkene 6a,w ec onducted ac ontrol reaction comprising only 4-chlorophenylhydrazine (5b)a nd Selectfluor (2). This reactiond id neither provide the sought-afterb y-product, nor compound 18; hence,i tb ecamec leart hat the former alkene 6a needed to be as tructural component of the by-product as well.…”

“…[12a] Starting from phenylhydrazines 5 and alkenes 6,t he first Meerwein-type carbofluorinationc ould be put into practice, in whicht he desired arylation products 7 [16] were obtainedb yt rapping of alkyl radical 8 by Selectfluor (2). In this reaction, the fluorines ource 2 previously serves also as an oxidantt og enerate aryl radicals 9 from 5.H owever,b esides 7,t his reaction led to an unknown by-product that we were unable to suppressd uring optimization, and which, we reasoned, could be formed because of the high reactivityo f3.Further evidence for the reactivity of 3 was provided by ar eport by Ritter [17] on an attractive new type of para-selective arene functionalization, in which radical dication 3 was assumed to playakey role in the attack onto arene 10 to give 11 (Scheme 1C).…”

Ruthenium‐Catalyzed para‐Selective C−H Alkylation of Aniline Derivatives

“…[2] Recent developments have allowed carefully tailored catalytic systems to permit meta-selective CÀH functionalization. [6] Accessing complementary para-selective methodologies typically takes advantage of electronic effects to permit C À H functionalization at the para position of an electron-rich arene,a sr eported in the pioneering reports from the groups of Gaunt, [7] Nicewicz, [8] and Ritter [9] (Scheme 1a). [6] Accessing complementary para-selective methodologies typically takes advantage of electronic effects to permit C À H functionalization at the para position of an electron-rich arene,a sr eported in the pioneering reports from the groups of Gaunt, [7] Nicewicz, [8] and Ritter [9] (Scheme 1a).…”